When nutrients are taken orally, there is greater insulin secretion than when the same amount of these nutrients are given intravenously. The factor(s) in the gastrointestinal (GI) tract which are responsible for enhancement of insulin secretion ("incretin(s)") have not been fully characterized. We have developed an isolated, perfused rat intestine preparation to apply to the search for such factor(s). Feeding this preparation a glucose solution or an electrolyte solution results in an enteric portal venous effluent (EPVE) which will enhance insulin secretion from the isolated, perfused pancreas of another rat. This enhancing factor is absent in EPVE of unfed gut or EPVE from fed gut of old rats. Known GI hormones have different effects on rat pancreas secretion when compared with EPVE. OBJECTIVES: 1) To continue physiologic studies of the effect of feedings upon the insulinotropic qualities of EPVE. We will compare EPVE effects with those of established and "candidate" GI hormones. 2) To initiate studies to determine whether gut-islet axis is deranged in diabetic rats and in man. 3) To develop chemical means of identifying the insulinotropic substances in EPVE.